Gastroesophageal reflux disease (GERD) is the most common disorder of the esophagus such that 5-7% of adult Americans experience its most common symptom (heartburn) on a daily basis. GERD tends to be a chronic disorder and is the leading indication for sales of proton pump inhibior (PPI) medications, amounting to more than $14 billion in the US in 2004. However, PPIs do not cure GERD, a condition with no recognized abnormality of gastric acid secretion. Rather, by reducing gastric acid secretion to abnormally low levels, PPIs partially compensate for the physiological abnormalities of GERD. Physiologically, GERD is characterized by incompetence of the esophagogastric junction (EGJ) with excessive reflux of gastric secretions into the esophagus. The impact of excessive reflux is compounded by poor esophageal clearance of that refluxate. The fundamental goal of this research project is to shift the paradigm of thought regarding GERD pathogenesis away from lower esophageal sphincter function per se and toward the anatomical and physiological factors that modulate sphincter function and ultimately lead to dysfunction;the earlier stages of pathogenesis. This application represents a collaborative effort by gastroenterologists (Dr Kahrilas and Dr Pandolfino), and mechanical engineers with long-standing interest in gastrointestinal physiology (Dr Brasseur and Dr Ghosh). Investigational methodologies include high-resolution solid-state manometry in conjunction with endoclip placement and synchronized with fluoroscopy, high resolution intraluminal impedance monitoring, intraluminal pH monitoring, and high frequency intraluminal ultrasound. Owing to the complexity of EGJ sphincteric function, a "computer laboratory" will be used to develop a mathematical model of the EGJ. Modelling will be based upon our experimental data to facilitate simulation of the complex interaction between anatomical and physiological variables affecting the EGJ. The key physiological properties targeted for investigation are the axial mobility and compliance of the EGJ. It is hypothesized that aberrations of both likely result from chronic mechanical stresses imposed by abdominal obesity and age- related change, ultimately undermining EGJ function. It is a fundamental goal of this research project to establish the physiological criteria for effective GERD therapy. A future direction for this research group will be to devise and test a "corrective intervention" based on those physiological objectives.